title: NMDA receptor-mediated long-term alterations in epileptiform activity in experimental chronic epilepsy.
abstract: When epileptiform activity is acutely induced in vitro, transient partial blockade of N-methyl-d-aspartic acid (NMDA) receptor-mediated calcium influx leads to selective long-term depotentiation of the synapses involved in the epileptic activity as well as a reduction in the probability of further epileptiform activity. If such selective depotentiation occurred within foci of epileptic activity in vivo, the corresponding long-term reduction in seizure probability could form the basis for a novel treatment of epilepsy. Continuous radiotelemetric EEG monitoring demonstrated modest acute anticonvulsant effects but no long-term reductions in the probability of spontaneous seizures after transient partial blockade of NMDA receptors (NMDAR) during ictal and interictal activity in the kainate animal model of chronic epilepsy. In vitro, depotentiation was induced when NMDAR were partially blocked during epileptiform activity in hippocampal slices from control animals, but not in slices from chronically epileptic rats. However in slices from epileptic animals, depotentiation during epileptiform activity was induced by partial block of NMDAR using NR2B- but not NR2A-selective antagonists. These results suggest that chronic epileptic activity is associated with changes in NMDA receptor-mediated signaling that is reflected in the pharmacology of activity- and NMDA receptor-dependent depotentiation.
authors.affiliation: Neuroscience Program, University of Colorado Health Sciences Center, United States.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Hellier
authors.forename: Andrew
authors.initials: A
authors.lastname: White
authors.forename: Philip A
authors.initials: PA
authors.lastname: Williams
authors.forename: F Edward
authors.initials: FE
authors.lastname: Dudek
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Staley
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D002908:Chronic Disease; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000379:methods; D004569:Electroencephalography / Q000379:methods; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000494:pharmacology; D036881:Long-Term Synaptic Depression / Q000187:drug effects; D008297:Male; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D013997:Time Factors; D014851:Wakefulness
chemical_list: D001713:Biphenyl Compounds; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D011422:Propionates; D016194:Receptors, N-Methyl-D-Aspartate; C104918:alpha-amino-2'-chloro-5-(phosphonomethyl)(1,1'-biphenyl)-3-propanoic acid; D007608:Kainic Acid